Use of an alkanoyl L-carnitine for the treatment of the erectile dysfunction

ABSTRACT

Erectile dysfunction is treated with a combination of propionyl L-carnitine in combination with sildenafil, apomorphine prostaglandin E1, pentolamine and papaverine.

The present invention relates to the use of an alkanoyl L-carnitine forthe treatment of the erectile dysfunction.

The erectile dysfunction (E.D.) is a syndrome characterised by apersistent inability to obtain or maintain a penis erection, for a timesufficient for a sexual intercourse.

The current knowledge indicates that the relaxation of the smoothmusculature of the corpus cavernosum which is necessary for the erectionis due to a non adrenergic, non cholinergic mechanism, mediated bynitric oxide (ON), in which prostaglandin (PG) is involved (MedicinaPratica, 2000; 12-16).

The relaxation of the smooth musculature of the corpus cavernosum andthe penis erection depend on a fine equilibrium between the effects ofvasoconstrictor and vasodilator factors.

To bring the penis to erection, it is necessary that the relaxation ofthe smooth musculature of the corpus cavernosum exceeds a determinedminimum level [Cardiovasc. Drugs Ther. 1991; 5 Supp (1): 77-83].

It has been shown that the basic defect in patients suffering from(E.D.) may be, independently from the aetiology, an imbalance betweenthe contraction and the capacity of the relaxation of the corpuscavernosum smooth musculature.

If the base tone of the corpus cavernosum smooth musculature is toohigh, the maximum relaxation level may not be sufficient to permit anhaematic flux sufficient for a normal erection.

If a minimum level of relaxation of the smooth musculature is notreached or maintained, the resistance to the venous runoff due to theintracavernous haematic pressure and the consequent compression of theveins will be insufficient for a normal erection.

In patients suffering from diabetes mellitus, the onset of an autonomicneuropathy is the main cause of the loss of the cholinergic activationduring the erectile process, with consequent reduction of the ON andprostaglandin release, furthermore, a reduced function of thenoradrenergic nervous ending could arise leading to a decrease of thevasodilator neurotransmitter levels such as the Vasoactive IntestinalPeptides (VIP).

In fact, it is recognised the role of the autonomic activation linked toa sexual excitation which leads to the release of nitric oxide (ON) andprostaglandin (PGI₂) exerted by the endothelium of the tissue cavernousof the penis as response to a cholinergic activation (Fed. Proc. 1982;41, 2858-62).

ON and PG activate a second messenger the cGMP (guanosin mono phosphatecyclic) which mediates a relaxant effect of the smooth muscle in thetrabecules of the cavernous tissue, thus permitting the haematic flux tofill the sinuses and lead to the penis tumefaction.

The exact contrary occurs under the effect of the adrenalin activitythrough the (α₁) adrenergic nervous endings In particular in the studyof the E.D. in diabetes mellitus it has been demonstrated that anendothelial impairment is responsible for the decreased “relaxation” ofthe trabecular smooth musculature of the corpus cavernosum which, innormal conditions, is mediated by the ON and that is the base of theorganic impotence.

It has been demonstrated that about 90% of patients suffering from TypeII diabetes mellitus show an E.D. [Diabetologia 2001, October 44, (10),1296-1301].

Previous uses of alkanoyl L-carnitines are already known.

In U.S. Pat. No. 5,811,457 the use of propionyl L-carnitine for treatingchronic obliterant arteriopathy is described.

In U.S. Pat. No. 6,063,820 the use of alkanoyl L-carnitines forpreparing a therapeutical nutritional composition for individualssuffering from diabetes mellitus is described.

In WO99/06039 the use of L-carnitine or an alkanoyl L-carnitine incombination with long chain aliphatic alcohols useful for the preventionand treatment of pathologies due to an altered lipid metabolism and anhigher platelet aggregation is described.

Further patents and publications describe the use of alkanoylL-carnitines for therapeutical scopes, but none of these publicationsdescribe or suggest the use of an alkanoyl L-carnitine, alone or incombination with other compounds, for treating the erectile dysfunction.

Compounds useful for treating erectile dysfunction are already known.For example, in Int. Urol. Nephrol 2001; 32 (3), 403-7 the use ofsildenafil for treating erectile dysfunction is described.

In Diabetologia 2001, October 44, (10), 1296-1301 the use of sildenafilfor treating erectile dysfunction in patients suffering from Type IIdiabetes mellitus is described.

In Salute Europa of Jun. 11, 2001 have been presented the first data(published in British Journal of Urology) relating to an Italian andEuropean clinical trial using sub-lingual apomorphine, for treatingerectile dysfunction.

Further publications describe the use of compounds useful for treatingerectile dysfunction, but none of them describe or suggest the use ofthese compounds in combination with an alkanoyl L-carnitine, fortreating said pathology.

Known compounds useful for treating the E.D. are not free ofdisadvantage.

For example, in Eur. Urol. 2001 August; 40 (2): 176-80 it is reportedthat not all patients respond to the treatment with sildenafil.

In Diabetologia 2001 October; 44 (10): 1296-301 it is reported that notall diabetic patients respond to the treatment with sildenafil.

In Salute Europa of Jun. 11, 2001, it is reported that not all patientsaffected by E.D. treated with apomorphine respond to this treatment.

In Hosp. Med. 1998 October; 59 (10): 777 and in Br. J. Urol. 1996October; 78(4): 628-31 it is reported that the administration ofprostaglandin E1 and of papaverine, respectively, is carried outintracavernously, and it is well known how troublesome is this way ofadministration.

The need to have new drugs, useful for the treatment of the erectiledysfunction, which do not present the disadvantages of the known drugs,is therefore very much felt.

It has now been found that the alkanoyl L-carnitines wherein thealkanoyl group, linear or branched, has 2-6 carbon atoms, or apharmaceutically acceptable salt thereof are useful agents for treatingthe erectile dysfunction.

What is meant by pharmacologically acceptable salt of an alkanoylL-carnitine is any salt of the latter with an acid that does not giverise to unwanted toxic or side effects.

These acids are well known to pharmacologists and to experts inpharmacy.

Non-limiting examples of pharmacologically acceptable salts of alkanoylL-carnitines are chloride, bromide, orotate, acid aspartate, acidcitrate, magnesium citrate, acid phosphate, fumarate and acid fumarate,magnesium fumarate, lactate, maleate, acid maleate, mucate, acidoxalate, pamoate, acid pamoate, acid sulphate, glucose phosphate,tartrate, acid tartate, magnesium tartrate, 2-amino ethansulphonate,magnesium 2-amino etansulphonate, Choline tartate and trichloroacetate.

Non-limiting examples of alkanoyl L-carnitines are acetyl, propionyl,butyryl, isobutyryl, valeryl and isovaleryl L-carnitine.

Preliminary experimental data related to the use of an alkanoylL-carnitine, propionyl L-carnitine, have shown that this compound isuseful for treating the erectile dysfunction, in diabetics or innon-diabetics patients, not previously treated with sildenafil.

It is therefore an object of the present invention the use of analkanoyl L-carnitine, or a pharmaceutical acceptable salt thereof, forpreparing a medicine for the treatment of erectile dysfunction.

A further object of the present invention is the use of an alkanoylL-carnitine for preparing a medicine for the treatment of erectiledysfunction in patients suffering from diabetes mellitus.

In both cases propionyl L-carnitine is preferred.

In the medical field it is known that specific drugs for treating E.D.which show not to be active (when used alone) on a particular group ofpatients in need of such drugs, they become active if combined betweenthem (Br. J. Urol 1996 May; 77(5): 736-9).

The following experimental data show that the compounds according to thepresent invention are suitable to be used in combination with furtherdrug useful for treating E.D.

According to the present invention by “useful drugs” it is intended anydrug useful for treating E.D.

It is therefore an object of the present invention the combination of analkanoyl L-carnitine with one or more drugs useful for treating erectiledysfunction.

A further object of the present invention are pharmaceuticalcompositions comprising as active ingredient an alkanoyl L-carnitine incombination with one or more of said useful drugs, and at least anexcipient and/or diluent pharmaceutically acceptable.

Non-limiting examples of said useful drugs are sildenafil, apomorphine,prostaglandin E1, pentolamine or papaverine.

A further object of the present invention is the use of an alkanoylL-carnitine, or a pharmaceutical acceptable salt thereof, in combinationwith one or more of said useful drugs, for preparing a medicine for thetreatment of erectile dysfunction.

A further object of the present invention is the use of an alkanoylL-carnitine in combination with one or more of said useful drugs, forpreparing a medicine for the treatment of erectile dysfunction inpatients affected by diabetes mellitus.

A further object of the present invention is the use of an alkanoylL-carnitine in combination with one or more of said useful drugs, forpreparing a medicine for the treatment of erectile dysfunction, whereinsaid patients do not respond to the treatment with said useful drugs.

A further object of the present invention is the use of an alkanoylL-carnitine in combination with one or more of said useful drugs, forpreparing a medicine for the treatment of erectile dysfunction inpatients suffering from diabetes mellitus, wherein said patients do notrespond to the treatment with said useful drugs.

Also in these further aspects of the present invention propionylL-carnitine is preferred.

The alkanoyl L-carnitines and the useful drugs above mentioned can beprepared for a simultaneous, sequential or separated administration.

Though the daily dose will depend, according to the judgement of theprimary care physician, on the patient's weight, age and generalcondition, it is generally advisable to administer 0.5 to 4 g/die ofalkanoyl L-carnitine or a stoichiometrically equivalent amount of one ofits pharmacologically acceptable salts. 1-2 g/die are preferred.

Larger doses can be administered in view of the alkanoyl L-carnitinessubstantial lack of toxicity.

Also the of administration regimen of the two active ingredients willdepend on the primary care physician's judgement, the patient's weight,age and general conditions, it is generally advisable to administer thealkanoyl L-carnitine daily and said combined useful drug twice weekly.

The following examples illustrate the invention.

EXAMPLE 1

In this trial, 24 diabetics patients suffering from E.D. which were notresponder to the treatment with sildenafil alone were enrolled.

2 g/day (1 g tablet twice a day) of propionyl L-carnitine were orallyadministered daily to the patients, and 50 mg sildenafil orally, twice aweek.

After 3 and 6 months from the beginning of the treatment controls weremade using the dynamic colour Doppler ultrasonography, these controlsshowed an improvement of the arterial flux which was coincident with asatisfactory clinical response evaluated with IIEF (Urology 1997June;49(6):822-30) in 60% of treated patients.

EXAMPLE 2

In this trial, 30 diabetics patients suffering from E.D. which were notresponder to the treatment with sildenafil alone were enrolled.

2 g/day (1 g tablet twice a day) of propionyl L-carnitine, were orallyadministered daily to the patients, and 50 mg sildenafil orally, twice aweek.

After 3 and 6 months from the beginning of the treatment controls weremade using the dynamic colour Doppler ultrasonography, these controlsshowed an improvement of the arterial flux which was coincident with asatisfactory clinical response evaluated with IIEF in 60% of treatedpatients.

1-12. (canceled)
 13. A method of treating erectile dysfunction whichcomprises administering to a patient in need thereof a combinationcomposition comprising as active ingredients propionyl L-carnitine or apharmaceutically acceptable salt thereof and a drug useful for thetreatment of erectile dysfunction selected from the group consisting ofsildenafil, apomorphine prostaglandin E1, pentolamine and papaverine.14. The method of claim 13, wherein the pharmaceutically acceptable saltof propionyl L-carnitine is selected from the group consisting ofchloride, bromide, orotate, acid aspartate, acid citrate, magnesiumcitrate, acid phosphate, fumarate, acid fumarate, magnesium fumarate,lactate, maleate, acid maleate, mucate, acid oxalate, pamoate, acidpamoate, acid sulphate, glucose phosphate, tartrate, acid tartrate,magnesium tartrate, 2-amino ethansulphonate, magnesium 2-aminoetansulphonate, choline tartrate and trichloroacetate.
 15. The method ofclaim 13 or 14, in which the erectile dysfunction patient is affected bydiabetes mellitus.
 16. The method of claims 13 or 14 in which theerectile dysfunction patient does not respond to treatment with drugsuseful for the treatment of erectile dysfunction.
 17. The method ofclaim 16, in which the drug useful for the treatment of erectiledysfunction is selected from the group consisting of sildenafil,apomorphine prostaglandin E1, pentolamine and papaverine.
 18. Apharmaceutical composition comprising, as active ingredients, propionylL-carnitine or a pharmaceutically acceptable salt thereof and a drugselected from the group consisting of sildenafil, apomorphineprostaglandin, pentolamine and papaverine and at least one excipientand/or pharmaceutically acceptable diluent.